1. Field of the Invention
The present invention relates generally to the treatment of cell proliferative diseases such as cancer. More particularly, it concerns caffeic acid and related analogs useful for the treatment of cell proliferative diseases such as cancer, methods of synthesis of these compounds, and methods of treatment employing these compounds.
2. Description of Related Art
The compound AG490 is a kinase inhibitor that inhibits Janus kinase 2/Signal transducer and activator of transcription-3 (Jak2/STAT3) signaling pathway. AG490 belongs to a group of compounds defined by the parent natural product caffeic acid and its natural derivatives like caffeic acid benzyl ester.

Targeted inhibition of the Jak2/STAT3 pathway with caffeic acid analogs such as AG490 inhibits tumor cell growth and increases sensitivity to apoptotic stimuli; thus, inhibitors of this pathway likely represent potential therapeutics for cancer therapy (Catlett-Falcone et al., 1999; Alas and Bonavida, 2003; Burdelya et al., 2002). AG490 would not be considered a drug-like molecule due to its instability in biological matrices (blood, tissues, etc) and a lack of potency (Kondo, et al, 2007; Burdelya et al., 2002; Meydan et al., 1996; Constantin et al., 1998). Receptor-based or direct activation of Jak2/STAT3 pathway by such stimulators such as EGF, scr, and IL-6 (multiple interleukins and cytokines) promoting survival proliferation and angiogenesis of human tumors (Bharti et al., Verma et al., Kerr et al.), requires inhibitors more potent and more stable than AG490 to have potential as anti-cancer drugs.
Jak2/STAT3 signaling pathways participate in the progression of a variety of malignancies. STAT3 is constitutively activated in pancreatic carcinoma, glioblastoma multiforme, and squamous cell carcinoma of the head and neck, among others, and its activation has been shown to affect VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. As such, STAT3 may be an excellent target for drug development (Yu and Jove, 2004). No effective inhibitors are currently available.
AG490, a caffeic acid analog, is sometimes referred descriptively as a tyrphostin. U.S. Pat. No. 6,426,366 and U.S. Patent Publication No. 2003/0013748 describe compounds that have structural similarity with AG490.
AG490, however, has limited activity in animal studies and must be used at high concentrations (˜50 to 100 μM) to achieve inhibition of Jak2/STAT3 signaling and anti-tumor effects. This low potency of AG490 is insufficient to warrant clinical investigation of this compound for the treatment of cancer (Burdelya et al., 2002; Meydan et al., 1996; Constantin et al., 1998). Thus a need exists for therapeutics that exhibit strong anti-proliferative effects through a similar mechanism at lower therapeutic concentrations.